Characterisation of the mechanisms underlying the special sensitivity of the CA2 hippocampal area to adenosine receptor antagonists

Abstract

Recent studies have underscored the importance of the CA2 area in social memory formation. This area, a narrow transition zone between hippocampal CA3 and CA1 areas, is endowed with special connectivity and a distinctive molecular composition. In particular, adenosine A₁ receptors (A₁R) are enriched in CA2, and based on the prominent synaptic potentiation induced by A₁R antagonists (e.g., caffeine) in this area, it has been proposed that CA2 is under the strong tonic control of A₁R activation. It is unclear whether this special sensitivity of CA2 to A₁R antagonists is due to an elevated extracellular concentration of adenosine or to a different A₁R function. Here, using the recording of field potentials evoked simultaneously in CA2 and CA1 by Schaffer collateral stimulation, we confirm that the application of A₁R antagonists, caffeine and DPCPX has a stronger effect on synaptic responses in CA2 than in those evoked in CA1. This difference was, at least partially, explained by the action of A₁R antagonists on presynaptic A₁Rs. We found that caffeine-induced potentiation in CA2 was restricted to Schaffer collateral synapses, but not to those formed by temporoammonic inputs. We also observed that the apparent affinity of an A₁R agonist is similar for A₁R in both CA2 and CA1 areas, which indicates that the tonic activation of A₁R in both areas is comparable. Furthermore, we show that the direct activation of adenylyl cyclase with forskolin in the presence of rolipram, a phosphodiesterase inhibitor, greatly enhances the synaptic potentials in CA2 compared to CA1. The forskolin-induced potentiation was exacerbated in the presence of caffeine or DPCPX, accentuating the differences between the two areas. These results indicate that the tonic activation of A₁Rs in area CA2 is not different to that of other hippocampal areas, but it is more efficiently coupled to the downstream effectors.

Keywords: Adenosine A(1) receptors; Adenylyl cyclase; Area CA2; Caffeine; Presynaptic inhibition; Synaptic potentiation.